Role of trefoil factor 1 in gastric cancer and relationship between trefoil factor 1 and gastrokine 1

Abstract

Abstract. Trefoil factor 1 (TFF1) is a small cysteine-rich secreted protein which is principally expressed in the superficial cells of gastric mucosa. In gastric cancer, TFF1 is downregulated and plays an important role. Gastrokine 1 (GKN1) is a secreted protein with similar expression and biological functions to TFF1. This study aimed to determine the expression and biological functions of TFF1 and the relationships between TFF1 and GKN1 in gastric cancer. RT-PCR and immunohistochemistry were performed to detect TFF1 expression in gastric cancer cell lines and tissues. The transfected and co-transfected AGS cells which stably expressed TFF1 or both TFF1 and GKN1 were generated. Phenotypic changes such as cell viability, apoptosis and cell cycle modulation were assayed in the transfected cells. We found that TFF1 expression was significantly downregulated or lost in gastric cancer cell lines, gastric dysplasia and cancer. Restoration of TFF1 expression in AGS cells suppressed tumor cell viability and arrested AGS cells in the G1-S transition phase after olomoucine treatment. However, TFF1 was unable to induce cell apoptosis. In co-transfected cells, we found that TFF1 and GKN1 did not directly interact at the protein level. GKN1 was unable to cooperate with TFF1 on cell viability suppression, cell apoptosis and differentiation. Together, these results indicate that TFF1 expression is significantly downregulated in gastric cancer. TFF1 inhibited cell proliferation by delaying G1-S phase transition but not by inducing apoptosis. TFF1 may not interact or cooperate with GKN1 at the protein and functional level. IntroductionGastric cancer is the second most common cause of cancer mortality worldwide (1-3). Although the molecular mechanisms of gastric cancer are still unclear, some molecular changes in the development of tumor were characterized. In recent studies, TFF1 is a spotlight molecule in gastric cancer. TFF1 is a 60-amino acid, highly conserved protein with a clover leaf-like structure formed by cysteine disulphide bonds and belongs to the trefoil factor family (4-6). TFF1 was found abundantly expressed in normal gastric mucosa. As a secreted protein, TFF1 protein was synthesized and secreted by the gastric epithelial cells and expressed in the upper part of the pits. In ulceration or inflammatory diseases, TFF1 induced epithelial restitution after injury and protects the integrity of the epithelial barrier (7-10). TFF1 was also involved in gastric carcinogenesis. In most gastric adenocarcinomas, the expression of TFF1 was downregulated or absent comparing to abundant in normal gastric mucosa (11,12). A previous study found that the TFF1-deficient mice were dysfunctional and showed severe hyperplasia and dysplasia, and all homozygous mutant mice developed antropyloric adenoma (13). Moreover, TFF1 demonstrated inhibition of cell growth and arrest of cell difference in gastric cancer (14,15). Thus, TFF1 is hypothesized as a tumor suppressor in gastric cancer. TFF1 was also involved in other human cancers such a...

Gastrokines: stomach-specific proteins with putative homeostatic and tumor suppressor roles

“…By serial analysis of gene expression, Oien et al (50,51) independently identified GKN1 as downregulated in gastric cancer and reported loss in 100% of cancers examined (8 of 8 cases, low numbers noted), including intestinal and diffuse subtypes. The finding of GKN1 mRNA and protein expression loss has since been replicated in several other gastric tumor cohorts (35,37,47,76). GKN2, although researched less intensively than GKN1, appears equally vulnerable to downregulation during gastric cancer development.…”

Immunoexpression of Trefoil Factor 1 in Non-Neoplastic and Neoplastic Canine Gastric Tissues

“…The role of TFF1 or pS2 in gastric carcinogenesis has been investigated in several human and mouse models, and it has been proposed that it might act as a tumor suppressor factor [24,28]. Previously, Campbell and Jabbes [29] have sequenced canine and feline TFFs cDNAs derived from gastric (TFF1, TFF2) and colonic (TFF3) mucosa RNA and showed that the majority of the deduced amino acid sequences of canine and feline TFFs obtained were in agreement with those of other mammalian species (e.g., human, rat, mouse, cow, pig, sheep), supporting the theory that the dog and cat may prove to be useful models for the study of trefoil peptides in various pathologies, such as IBD and gastrointestinal carcinomas.…”

“…In human gastric tissues, the expression of TFF1 has been found decreased in IM and adenomas compared with adjacent normal mucosa, and completely lost in about 40% to 60% of the carcinomas [12,[25][26][27]. Thus, it has been proposed that TFF1 functions as a gastric tumor suppressor gene [28].…”

Gastric cancer biomarkers; A systems biology approach

“…Likewise, cellular tumor antigen p53 involved predominantly in cell division regulation and apoptosis induction, mutates in most cancers [8] , [9] , [10] . As such, Gastrokine (GKN1) reducing the expression of gastrin-CCKBR signaling pathway is capable of preventing gastric cancer [11] , [12] , [13] , [14] . This protein can also prevent the invasion of cancer cells into other tissues through inactivation of NF-kappaB pathway [15] .…”